Congestive heart failure (HF) in the U.S is the leading cause of death, and the major cause of HF is myocardial ischemic disease. Therefore, improvement of therapy post myocardial infarction (Ml) is extremely important, and the development of a new class of medicine that prevents the progression of HF would have a large market opportunity, representing a significant clinical advance. Additionally, most of these patients have elevated blood lipids and many have impaired glucose metabolism and are either diabetic or pre-diabetic. Therefore, a HF drug which can exert a favorable effect on diabetes control will have a unique niche in the HF market. The goal of this grant proposal is to demonstrate the efficacy of a new class of HF drugs, with a mechanism of inhibition of type 5 adenylyl cyclase (ACS), to improve the adverse effects of remodeling following chronic Ml and to simultaneously improve disorders of glucose metabolism,. This proposal is based on our prior work in a mouse model with disruption of the ACS gene, i.e., ACS knockout mice (ACS KO), and based on the utilization of a specific pharmacological ACS inhibitor. ACS KO mice have prolonged lifespan and are protected from the cardiomyopathy of aging. They are also protected against the development of HF induced by either chronic pressure overload, or by excessive sympathetic stimulation. Another unique feature of the ACS KO mouse model is its ability to increase coronary reserve, which should be particularly useful in preventing the development of HF. Importantly for this proposal these mice eat more than wild type, but weigh less, which points to a favorable metabolic profile, confirmed by our preliminary data using a specific pharmacological ACS inhibitor. In our preliminary screening for ACS inhibitors, adenine 9-?-D-arabinofuranoside (AraAde, also known as Vidarabine or Vira-A(r)), which was used in the clinic for a different indication, i.e., treating viral infections, showed potent and selective inhibition of ACS. Furthermore, our preliminary data demonstrate that the pharmacological AC 5 inhibitor protects against HF following chronic Ml and also protects against development of hyperglycemia induced by a high-fat diet in mice, suggesting that inhibition of ACS improves glucose metabolism in addition to its salutary effects in protecting against HF. Accordingly, in this preclinical study, we will examine the effects of AraAde on post-MI HF with or without impaired glucose metabolism. In addition we will examine the efficacy of this drug in the best pre-clinical model for HF, the chronically instrumented, conscious monkey post-MI.

Public Health Relevance

Almost 5.5 million patients are diagnosed with congestive heart failure in the U.S and the major cause of HF is myocardial ischemic disease. However, no effective therapy has been established to treat congestive HF. The current investigation is aimed at generating a new class of medicine that will prevent progression of HF. Due to the large number of patients with this condition, this may have a significant impact on public health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory Grants (P20)
Project #
5P20HL101420-02
Application #
8010655
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (F1))
Program Officer
Schwartz, Lisa
Project Start
2010-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$779,111
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Ho, David; Chen, Li; Zhao, Xin et al. (2012) Smooth muscle myosin inhibition: a novel therapeutic approach for pulmonary hypertension. PLoS One 7:e36302
Gao, Shumin; Ho, David; Vatner, Dorothy E et al. (2011) Echocardiography in Mice. Curr Protoc Mouse Biol 1:71-83
Zhao, Xin; Ho, David; Gao, Shumin et al. (2011) Arterial Pressure Monitoring in Mice. Curr Protoc Mouse Biol 1:105-122
Ho, David; Zhao, Xin; Gao, Shumin et al. (2011) Heart Rate and Electrocardiography Monitoring in Mice. Curr Protoc Mouse Biol 1:123-139
Zhao, Xin; Ho, David; Abarzua, Patricio et al. (2011) Inhibition of smooth muscle myosin as a novel therapeutic target for hypertension. J Pharmacol Exp Ther 339:307-12
Kudej, Raymond K; Fasano, Mathew; Zhao, Xin et al. (2011) Second window of preconditioning normalizes palmitate use for oxidation and improves function during low-flow ischaemia. Cardiovasc Res 92:394-400
Ho, David; Yan, Lin; Iwatsubo, Kousaku et al. (2010) Modulation of beta-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5. Heart Fail Rev 15:495-512